Endoplasmic reticulum unfolded protein response

The endoplasmic reticulum unfolded protein response (UPR-ER) matches the folding capacity of the ER to the load of client proteins entering it. In animals ER stress is sensed by three ER-membrane transducers. The kinase-endoribonuclease IRE1 removes a small intron from the XBP1 mRNA, and the spliced mRNA encodes the active bZIP transcription factor XBP1s, which induces chaperone, folding and ER-associated degradation genes, including the BiP gene. The eIF2alpha kinase PERK phosphorylates eIF2alpha to attenuate general translation and so reduce client load; reduced ternary complex favours translation of the uORF-containing ATF4 mRNA, and ATF4 then activates cytoprotective genes. ATF6 is an ER-membrane-anchored bZIP factor that is released by intramembrane proteolysis and enters the nucleus. The ER HSP70 BiP is both a luminal folding chaperone and a UPR target, and its binding to the luminal domains of the transducers keeps them inactive until misfolded proteins compete it away. The IRE1 arm is the ancestral eukaryotic core: budding yeast has only Ire1 and its spliced-mRNA target Hac1, an unrelated bZIP factor that plays the XBP1 role, while the PERK and ATF6 arms are animal additions. The arms are partly redundant; in C. elegans, loss of the IRE1-XBP1 arm together with PERK or ATF6 causes larval arrest, and neuronal XBP1s can activate the UPR-ER in distant tissues.

Boundary. This module covers the three UPR-ER transducer arms (IRE1/XBP1, PERK/eIF2alpha/ATF4 and ATF6) and the ER HSP70 BiP, which is both a regulator of the transducers and a transcriptional output. It has four parts. It replaces the earlier C. elegans-only module MODULE:c_elegans_er_unfolded_protein_response; all worm members and their evidence are kept as representative members. Taxon scope. The module context is Metazoa (NCBITaxon:33208), the clade over which the three-arm boundary holds. The IRE1 arm is older: PAINT node PTN000359335 places IRE1-mediated UPR at an ancestral eukaryotic IRE1 node (donors include plant, fungal, fly and mouse genes). Its output varies by lineage and is modeled as the variant set ire1_output_transcription_factor (XBP1 in animals, the unrelated bZIP Hac1 in budding yeast). The yeast variant documents the ancestral single-arm core and lies outside the module's metazoan context. Yeast Ire1 also binds unfolded proteins directly, whereas mammalian IRE1alpha activation depends mainly on BiP release (PMID:19538957). The tRNA ligase that completes splicing (yeast Trl1; RtcB in animals) is not modeled. Representatives. Each role is a FAMILY selector with the worm protein and one human exemplar (plus yeast Ire1 and Hac1 for the IRE1 arm). All accessions follow their gene reviews (worm ire-1 Q09499, xbp-1 G5EE07, pek-1 Q19192, eif-2alpha Q9BKU3, atf-4 Q22156, atf-6 Q20435, hsp-4 P20163, hsp-3 P27420; human ERN1 O75460, XBP1 P17861, EIF2AK3 Q9NZJ5, ATF4 P18848, ATF6 P18850, HSPA5 P11021; yeast IRE1 P32361, HAC1 P41546). PANTHER family ids are those that UniProt assigns to every listed representative; PERK sits in the broad eIF2alpha kinase family PTHR11042 (which also contains GCN2, HRI and PKR), so that family term is wider than the role; UniProt places worm PEK-1 and human PERK in different subfamilies (SF91, SF166). BiP is grounded on the BiP subfamily PTHR19375:SF380 of the HSP70 family. Transcription factor terms. The XBP1 and ATF6 annotons use DNA-binding transcription activator activity (GO:0001228) as chosen by the human XBP1 and ATF6 reviews; the worm xbp-1 and atf-6 reviews use the parent term GO:0000981, and the yeast HAC1 review also uses GO:0000981. Human XBP1 acts as the spliced isoform XBP1s (P17861-2 in GO-CAM gomodel:689e7a5d00000567). eIF2alpha. eIF2alpha (worm EIF-2alpha, Q9BKU3) is modeled as a participant of the PERK arm, following its gene review, which places it in the PERK-mediated UPR on the grounds that phosphorylated eIF2alpha does the attenuation work: it converts eIF2 into an inhibitor of its own recycling by eIF2B. The function term is its ordinary translation initiation factor activity (GO:0003743), negatively regulated by PERK. GO has no molecular-function term for the inhibitory activity of phosphorylated eIF2 toward eIF2B, so the annoton records the participant correctly but not the attenuating activity itself; this tension is noted on the annoton and is an ontology question, not a knowledge gap. Human EIF2S1 has no gene review and is not listed. Integrated stress response. GCN2 is a second eIF2alpha kinase activated by amino-acid limitation and, in worms, by mitochondrial stress (PMID:22719267, PMID:23692540), not by ER stress. It belongs with the integrated stress response, of which the PERK branch is the ER-specific input. ATF4 is included as the output of the PERK branch; in mammals PERK dependence of ATF4 translation is shown (PMID:11106749), but in C. elegans the dependence of ATF-4 induction on PEK-1 itself has not been tested (see knowledge_gaps). Its process term is integrated stress response signaling, following the atf-4 review. Left out. Site-1 and Site-2 proteases that process ATF6 in mammals (PMID:11163209) are activation machinery and are not modeled as parts (C. elegans has no clear S1P homolog, PMID:16184190). The C. elegans ABU/PQN "activated in blocked UPR" genes (PMID:12186849) are a compensatory response in xbp-1 mutants. The neuronal signal for cell-non-autonomous UPR-ER activation in worms (small clear vesicle release, PMID:23791175) is inter-tissue regulation and not modeled as a part. ERAD and ER-phagy are downstream proteostasis outputs. Related modules. The mitochondrial UPR is MODULE:mitochondrial_upr and the HSF1 cytosolic heat shock response is MODULE:heat_shock_response. GO-CAM. C. elegans model gomodel:5b528b1100000489 links IRE-1 RNA endonuclease activity to XBP-1 in intestine and neurons. Human models gomodel:689e7a5d00000567 (IRE1, BiP sequestering, XBP1s), gomodel:66b5638000000624 (PERK and ATF4) and gomodel:66b5638000000739 (BiP inhibition of PERK) are linked on the matching annotons.